1. Neonatal Abstinence Syndrome Lauritz Meyer, MD September 11, 2015 SDPA Conference

2. Disclosure I have no financial relationships to disclose.

3. Objectives Describe the incidence of Neonatal Abstinence Syndrome in the United States Identify common symptoms of Neonatal Abstinence Syndrome Familiarize with scoring systems for Neonatal Abstinence Syndrome Identify treatment strategies for Neonatal Abstinence Syndrome

4. Neonatal Abstinence Syndrome Defined as a group of clinical signs and symptoms in a neonate resulting from prolonged exposure to illicit or prescribed drugs Also called Neonatal Drug Withdrawal Short term syndrome but may have long lasting effects Can be caused by in-utero exposure or iatrogenic exposure in hospitalized neonates

5. Opiate History Opium derived from the poppy First records of opium addiction are from the late 18 th century Increase in opioid addiction among women noted in the 19 th century

6. Opiate History Morphine isolated in 1804 o Use among women was associated with sterility Heroin synthesized in 1874 Initially thought addiction among women did not affect infants

7. Opiate History 1875: first reported case of neonatal abstinence o More over years, most died, no specific treatment 1903: First report of neonate surviving abstinence after Tx with morphine o Called Congenital Morphinism 1947: Seizures in a baby with Congenital Morphinism were successfully treated with morphine o Led to increased awareness and name changed to Abstinence Syndrome in Neonates

8. Opiate History Methadone: Introduced in 1964 as a replacement treatment for opioid addiction Methadone clinics became very common for treating recovering heroin addicts Initially thought to not cause withdrawal in neonates, likely secondary to increased half life but since has become a common cause of NAS

9. Opiate History Buprenorphine: Approved as an alternative to methadone for opioid addiction in U.S. in 2002 o Sublingual tablets Also leads to NAS o May cause less severe NAS symptoms than methadone

10. Illicit Drug Use in the U.S. 2013 National Survey on Drug Use and Health o 9.4% of population age 12 and older used illicit drugs within the past month (24.6 million individuals) o 5.4% of pregnant women aged 15-44 were current illicit drug users 14.6% in age 15-17 year olds 9% in the first trimester 4.8% in the second trimester 2.4% in the third trimester o 22.9% of population age 12 and older were binge alcohol users in the past month (60.1 million individuals) 6.3% were defined as heavy drinkers o 9.4% of pregnant women were current alcohol users, 2.3% were binge drinkers, and 0.4% were heavy drinkers

11. Illicit Drug Use in the Upper Midwest 2013 National Survey on Drug Use and Health o South Dakota 6.17% of 12 years and older have used illicit drugs in the past month (42 thousand individuals) o Minnesota 7.63% of 12 years and older have used illicit drugs in the past month (343 thousand individuals) o Iowa 7.34% of 12 years and older have used illicit drugs in the past month (188 thousand individuals)

12. Incidence of NAS Rising Incidence has nearly doubled in the past 15 years based on national ICD-9 coding Becoming more widespread o No longer just inner cities o Increased use of prescription pain medications in pregnant women o Improved recognition of NAS

13. NAS Causing Drugs Opioids o Morphine, Methadone, Hydromorphone, Fentanyl, Heroin CNS Depressants o Benzodiazepines, Alcohol, Barbiturates CNS Stimulants o Amphetamines, Cocaine, Nicotine, Caffeine Hallucinogens o LSD, inhalants, mescaline Polysubstance use SSRIs

14. Opioids Among the world’s oldest known drugs o Use of opium poppy goes back milennia Three types: natural, endogenous, and synthetic Produces analgesia by binding to mu-opioid receptors in the CNS, PNS, and GI system o Leads to inhibition of noradrenaline release Effects include: o Sedation o Euphoria o Respiratory depression o Decreased GI motility Long term use leads to physical dependence

15. Opioids Withdrawal o The initial condition that led to the diagnosis of NAS o Abrupt discontinuation leads to: Massive release of noradrenaline Leads to autonomic, behavioral, and GI symptoms/signs o Timing, presentation, and severity of symptoms dependent upon maternal and neonatal factors Drug, dosage, time since last use, placental transfer, metabolism Mu-opioid receptor (OPRM1) and catechol-o-methyltransferase (COMT) gene genetic variations affect the need for and the length of treatment

16. Opioids Neonates exposed in-utero have signs/symptoms of opioid withdrawal 55-94% of the time Addition of other maternal or neonatal medications, neonatal diet, and environmental stimuli can affect the severity and incidence of NAS Symptoms can present within the first 24 hours of life, or be delayed for 7 days or longer o Dependent on type of drug, metabolism, etc.

17. Clinical Symptoms of NAS due to Opioids Gastrointestinal o Vomiting/diarrhea o Poor feeding o Uncoordinated suck o Constant sucking o Dehydration o Poor weight gain/FTT Autonomic o Excessive sweating o Temperature instability o Nasal stuffiness o Mottling o Yawning Neurologic o Tremors o Irritability o Increased wakefulness o High-pitched cry o Hypertonicity o Hyperactive reflexes o Exaggerated Moro o Seizures o Frequent sneezing/yawning

18. Video https://www.youtube.com/watch?v=2eP5EnFSG0c

19. Clinical Symptoms (cont.) Seizures occur in 2-11 percent of NAS cases EEG abnormalities have been seen in up to 30% of NAS cases attributed to opioids Increased incidence of Small for Gestational Age (SGA) births Increased incidence of respiratory difficulties

20. Timing of Withdrawal Wide variation dependent upon the half-life of the drug and the recent history of drug use Symptoms can present within the first 24 hours for short half life drugs (Heroin), but may not present for 72 hours up to 7 days or longer for long half life drugs (Methadone, Buprenorphine) Neonates born to mothers who have gone >7 days from last use are at much lower risk for NAS, but still require close monitoring

21. Methadone Common prescription drug used for recovering Heroin addicts Long half life leads to delayed presentation of NAS symptoms for several days Higher daily doses are more likely to lead to NAS o >95% of infants will develop symptoms with doses >20mg/day Difficult to wean mothers during pregnancy due to high risk of fetal complications with abrupt dose changes

22. Buprenorphine Increasing use for opiate withdrawal including during pregnancy Lower transplacental transfer due to higher molecular weight o Thought to lower the incidence and severity of NAS Decreased length of stay for infants with NAS Subutex – buprenorphine only Suboxone – buprenorphine plus naloxone to guard against misuse

23. Fentanyl Use of transdermal patch increasing for treatment of chronic pain Short half life leads to rapid symptoms of NAS in the first 24 hours Risk of rapid withdrawal for mother if lose access to supply of patches Breastfeeding a concern due to risk of rapid withdrawal

24. Depressants Alcohol withdrawal can present 3-12 hours after birth May show symptoms of NAS similar to opioid withdrawal although usually more mild Benzodiazepine withdrawal can have a variable onset dependent upon half life and dosage

25. Stimulants Methamphetamine and cocaine have low rates of NAS requiring therapy Symptoms at birth more likely the result of drug effects vs withdrawal o Similar symptoms to opioid NAS – tremors, irritability, poor sleep pattern, excessive sucking, etc High rates of prematurity and IUGR status Increased risk of placental abruption Common to see polysubstance use

26. SSRIs Used in 7-13% of pregnancies 10-30% risk of Poor Neonatal Adaptation Syndrome Tremors, increased tone, high pitched cry, poor sleep patterns are common symptoms Increased rate of respiratory distress Increased risk of PPHN Generally presents in the first 48 hours of life and resolve within another 48 hours Paroxetine (Paxil) carries the highest risk

27. Withdrawal vs Toxicity Withdrawal: o Symptoms develop as the amount of drug decreases, indicative of dependence on the drug o Most common with opioids, but also with depressants and SSRIs Toxicity: o Symptoms present early and decrease as the drug is metabolized o Most common with stimulants such as cocaine or methamphetamine

28. Premature Infants Lower risk of developing NAS <35 weeks Central Nervous System developmentally immature o Motor dysfunction less able to be expressed Lower total drug exposure in-utero Lower fat stores limits build up in the body Lack of accurate assessment tools to identify symptoms in premature infants – all assessment tools created for term infants Risk decreases with decreasing GA

29. Iatrogenic NAS Many NICU patients are exposed to opioids and benzodiazepines during their stay (surgical, sedation for PPHN, ect.) May develop after 5-7 days of exposure to fentanyl/morphine or benzodiazepines Important to recognize the risk and treat these infants similar to in-utero exposure to avoid adverse outcomes

30. What To Do? Neonate is at risk for NAS based on known exposure history or has other risk factors that are concerning for possible NAS Drug Screen Initiate abstinence scoring system Close observation

31. Drug Screening Urine o Low sensitivity due to need for a recent exposure to show positive o Rapid turn around time (within 24 hours) Meconium o High sensitivity and specificity o Slow turn around time (days to a week) o May miss meconium if stooled in-utero or at birth and not collected Umbilical Cord o Increasing use o Not dependent upon collection of urine or meconium o Eliminates possibility of false positive secondary to exposure after birth

32. Abstinence Scoring Several scoring systems are available with no clear standard Not drug specific – primarily for opiates Most hospitals choose one and adapt to their needs Two most common: Finnegan Neonatal Abstinence Scoring System, Neonatal Withdrawal Scoring System (Lipsitz) Others available: Ostrea criteria, Neonatal Withdrawal Inventory, Riley Infant Pain Scale

33. Finnegan

34. Finnegan Most widely used scoring system Comprised of 20 most common signs and grouped into CNS, metabolic/respiratory, and GI categories Each symptom assigned a score based on significance and potential for harm Cumulative score of 7 or less considered mild NAS without need for pharmacologic treatment Scores >8 suggest careful monitoring and likely need for pharmacotherapy

35. Lipsitz Assigns a score of 0 to 3 for tremors, irritability, reflexes, stools, muscle tone, skin abrasions, and tachypnea Assigns a score of 0 to 1 for frequent sneezing, frequent yawning, and vomiting or fever A score of 5 or greater suggests opiate exposure A score of 8 or greater indicates need for pharmacotherapy

36. Treatment Goals of treatment: o Allow the infant to withdraw without excessive excitation that can lead to withdrawal symptoms o Especially important to avoid the most severe, i.e. seizures o Establish a physiologic sleep pattern o Establish consistent weight gain o Allow the infant to communicate needs with caregivers o Help the infant manage new stimuli in its new environment

37. Non-pharmacologic Treatment First line therapy is ALWAYS non-pharmacologic Required for all infants with suspected NAS Keep environmental stimulation to a minimum o Low light o Quiet environment Swaddling Gentle handling with cares/cluster cares Quick response to symptoms Demand feeding ***Cuddlers***

38. Non-pharmacologic treatment Many large centers with a high population of NAS cases have a specific section or completely separate NICU dedicated to the care of NAS babies Nursing care with experience in caring for NAS babies is crucial to help ensure a safe and swift recovery

39. Pharmacotherapy Decision to initiate pharmacotherapy based on abstinence scoring and the known or suspected drug exposure Indicated when non-pharmacologic treatment is insufficient Indicated for moderate/severe symptoms Required to prevent severe complications, i.e. seizures

40. Pharmacotherapy Drawbacks: o Increases length of drug exposure o Increases length of stay o May impact maternal-infant bonding as a result Benefits: o Decreases the acute signs of NAS o Decreases the risk of severe complications like seizures or failure to thrive

41. Pharmacotherapy Ideally treat with the same class of drug as that causing NAS Choice can be a challenge when drug of exposure is unknown or in setting of polysubstance use

42. Pharmacotherapy Mainstay of therapy has been opioids Opioids are first line treatment based on available evidence Historic use of tincture of opium and paregoric have fallen out of favor due to safety concerns Morphine and Methadone are the two most common opioids used to treat NAS Buprenorphine is a potential option but limited safety and efficacy data in neonates o Sublingual dosing appeal

43. Pharmacotherapy - Morphine Variety of dosing regimens available for Morphine High dose o 0.08-0.1 mg/kg every 4 hours PO Low dose o 0.03-0.04 mg/kg every 4 hours PO With either regimen, the dose may be increased by 20% every 8 hours until symptoms are well controlled Typical maximum dose is 0.2 mg/kg/dose Other regimens include escalation by changing to every 3 hour dosing

44. Pharmacotherapy - Morphine Weaning is individualized to each patient Typical approach is to maintain current dose when adequate symptom control is achieved After 48-72 hours of stability may begin weaning Wean by decreasing dose by 20% every other day May require delayed taper or escalation if symptoms worsen

45. Pharmacotherapy - Methadone Typical starting dose of 0.05-0.1 mg/kg every 6 hours PO Adjust doses up and down by ~20% as needed similar to Morphine May require less frequent adjustments since half life is longer and effects of dose changes may be slower to manifest than with Morphine

46. 2 nd Line Treatment Used for severe NAS that is not controlled with a first line agent Phenobarbital o Most commonly used second line drug Diazepam o First line if the known cause of NAS is a benzodiazepine Clonidine o Used to avoid the sedative effects of phenobarbital

47. Phenobarbital Preferred medication for non-opiate NAS GABA agonist Does not prevent seizures at typical NAS doses Minimal benefit for GI symptoms Usual dose: 16 mg/kg loading dose, then 2-8 mg/kg/day divided BID for maintenance Route: Oral, IV, or IM Continue treatment until Morphine or Methadone are weaned off before weaning phenobarbital Taper phenobarbital by 10-20% per day

48. Diazepam Requires caution due to limited capacity of infants to metabolize Contains sodium benzoate o Requires monitoring for jaundice as it may displace bilirubin for conjugation and excretion Initial dose 1-2 mg every 8-12 hours May also consider lorazepam or midazolam dependent on preference and experience

49. Clonidine Effective adjunctive medication with opioids in shortening the duration of treatment Centrally acting alpha adrenergic agonist Requires monitoring for hypotension and bradycardia Initial dose 0.5-1 mcg/kg followed by 3-5 mcg/kg/day divided every 4-6 hours Requires taper due to risk of hypertension and tachycardia with abrupt discontinuation

50. Naloxone Contraindicated in the treatment of NAS due to the risk for rapid and severe NAS symptoms May precipitate seizures in some neonates

51. Iatrogenic NAS Treat with same drug class that was used for pain control/sedation Calculate total daily cumulative dose and divide into a schedule of equivalent medication o Do not forget PRN doses!!

52. Nutrition and NAS May have increased metabolic demands o May require significant increase in kcal/kg/day to offset losses from NAS o Fortified feeds Ad lib demand schedule o Prompt response to hunger cues important o May be frequent, small volume feeders Requires close monitoring of weight gain/loss and fluid status o Vomiting and loose stools may lead to increased fluid requirements PO intake may be poor N o NG supplementation or IV hydration

53. Breastfeeding Low rates of breastfeeding among NAS affected neonates AAP supports breastfeeding in appropriate situations May help with withdrawal symptoms Requires strict adherence and review of risks and benefits with the mother before initiation

54. Breastfeeding Allowed Ok to breastfeed when mothers are on a stable dose of methadone or buprenorphine o Low doses excreted in breastmilk Mothers who are in a treatment program prior to delivery or are enrolled into a program at birth o Requires strict adherence to the program with continued close follow up No other contraindications to breastfeeding

55. Breastfeeding Contraindications Polysubstance abuse or history of non-adherence to treatment programs HIV or other infectious risk Mothers taking hydrocodone or oxycodone o Require closer monitoring as these drugs are highly excreted in breastmilk Any illicit drug use during the 30 day period prior to delivery

56. Breastfeeding Best to follow strict feeding protocols to ensure a similar amount of breastmilk is provided each day Have mothers pump and provided pumped breastmilk early on to ensure consistent volumes o Provide for 1-2 feeds on day 1, and gradually increase as supply increases over the following days Discontinuation of breastfeeding o Important to stress weaning off of breastmilk as abrupt discontinuation may precipitate NAS symptoms at that time

57. Discharge and Follow Up Infants at risk for NAS require in-hospital monitoring until past the window for severe withdrawal Dependent upon the drug exposure o With known history of short half life drugs such as morphine or hydrocodone, may be discharged after 72 hours o With known history of long half life drugs such as methadone, may be discharged after 5-7 days Follow up visit should be scheduled within 2 days of discharge to ensure continued close monitoring

58. Discharge after Treatment Infants requiring pharmacotherapy: o Discharge frequently delayed until fully weaned off of medications with an adequate observation period off pharmacotherapy to ensure no rebound NAS o Discharge while still on therapy is an option if parents are reliable, taper is easily followed, and adequate follow up is assured o Extensive education about non-pharmacologic measures for treatment of symptoms and strict criteria for seeking evaluation are vital at discharge

59. Prenatal Counseling Important to be empathetic and nonjudgemental Teratogenicity o Opioids and stimulants can cause SGA status, prematurity, abruption, SAB o Cocaine and methamphetamine may lead to long term neurodevelopmental issues Expected Clinical Course o Observation for at least 3-7 days for signs and symptoms of NAS o Non-pharmacologic therapy is the primary treatment o Pharmacotherapy will require treatment that may last weeks to months

60. Prenatal Counseling Breastfeeding o Breastfeeding may be suitable in certain situations dependent upon the drugs used o Breastfeeding may help decrease NAS symptoms o Helpful to have a breastfeeding plan prior to delivery Social Concerns o Vital to discuss the importance of caregiver involvement in treatment of NAS o Adherence to follow up schedule and treatment recommendations will be vital to outcomes

61. Take Home Points NAS is a common condition in newborns and the incidence is rising Close monitoring is vital for infants at risk of NAS Infants who demonstrate symptoms without known risk factors require evaluation for NAS Non-pharmacologic measures are the first line therapy for NAS Breastfeeding is not contraindicated in NAS in some situations and can be beneficial in NAS treatment

62. References Avery’s Diseases of the Newborn, 9 th Ed. 2012 Burgos A, Burke B. Neonatal Abstinence Syndrome. NeoReviews. 2009;10(5)e222-229. Kocheriakota P. Neonatal Abstinence Syndrome. Pediatrics. 2014;134(2):e547-561. Tolia V, Patrick S, Bennett M, et al. Increasing Incidence of the Neonatal Abstinence Sydrome in the U.S. Neonatal ICUs. NEJM. 2015;372(22)2118-2126. Jansson L. Neonatal abstinence syndrome. UpToDate. 2015. Patrick S, Davis M, Lehman C, Cooper W. Increasing incidence and geographic distribution of neonatal abstinence syndrome: United States 2009-2012. J Perinatology. 2015. 1-6. 2013 National Survey on Drug Use and Health. http://www.samhsa.gov/data/population- data-nsduh